Abstract
BackgroundCD40 and its ligand (CD40L) play a critical role in co-ordinating immune responses. CD40 is also expressed in lymphoid malignancies and a number of carcinomas. In carcinoma cells the physiological outcome of CD40 ligation depends on the level of receptor engagement with low levels promoting cell survival and high levels inducing cell death. The most profound induction of cell death in carcinoma cells is induced by membrane-bound rather than recombinant soluble CD40L, but like other TNF family ligands, it is cleaved from the membrane by matrix metalloproteinases.ResultsWe have generated a replication-deficient adenovirus expressing a mutant CD40L that is resistant to metalloproteinase cleavage such that ligand expression is retained at the cell membrane. Here we show that the mutated, cleavage-resistant form of CD40L is a more potent inducer of apoptosis than wild-type ligand in CD40-positive carcinoma cell lines. Since transgene expression via replication-deficient adenovirus vectors in vivo is low, we have also engineered a conditionally replicating E1A-CR2 deleted adenovirus to express mutant CD40L, resulting in significant amplification of ligand expression and consequent enhancement of its therapeutic effect.ConclusionsCombined with numerous studies demonstrating its immunotherapeutic potential, these data provide a strong rationale for the exploitation of the CD40-CD40L pathway for the treatment of solid tumours.
Highlights
CD40 and its ligand (CD40L) play a critical role in co-ordinating immune responses
We have previously found that recombinant soluble CD40L (rsCD40L) can stimulate survival signalling pathways and induces apoptosis in carcinoma cells only in the presence of either protein synthesis inhibition, cytotoxic drugs or inhibitors of the PI3K/mTOR
Each cell line was infected with either RAdMock or RAdCD40L or left uninfected as a negative control and 48 hours later cell viability was assessed by WST-1 assay
Summary
CD40 and its ligand (CD40L) play a critical role in co-ordinating immune responses. CD40 is expressed in lymphoid malignancies and a number of carcinomas. In carcinoma cells the physiological outcome of CD40 ligation depends on the level of receptor engagement with low levels promoting cell survival and high levels inducing cell death. CD40 stimulation can effect the key elements required for generation of antigen-specific cytotoxic T-cell responses. On this basis, engagement of CD40 on DC to induce anti-tumour immune responses is a prolific area of research and both recombinant soluble CD40 ligand and CD40 agonist antibodies have entered clinical trials. In carcinoma cells the level of CD40 engagement influences the physiological outcome with low levels of ligation promoting cell survival/proliferation and high levels inducing growth arrest/apoptosis [3,4,5]. The precise form of the CD40 stimulus affects these responses with the most profound effects in carcinoma cells being induced by membrane-bound (mCD40L) rather than recombinant soluble CD40L (rsCD40L) [6,7]
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